Certain medical treatments involve the injection of particles into the blood of a patient. This is the case in particular for MRI contrast agents. The same will apply in the future to mediators for magnetic hyperthermia. The particles are generally injected in the form of colloidal dispersions, and it is necessary for these dispersions to be stable.
A dispersion can be stabilised either by electrostatic repulsion or by steric repulsion.
A dispersion stabilised by electrostatic repulsion cannot be used for an injection, because the charged particles would be eliminated immediately by the immune system. Furthermore, iron oxide has an isoelectric point (pH value for which the surface charge density is zero) of 7. Thus under physiological pH conditions the iron oxide nanoparticles are not charged and are therefore precipitated.
A dispersion stabilised by steric repulsion is obtained in particular by grafting of hydrophilic macromolecules on the surface of the particles.
Iron oxide particles are known which are coated with a layer of hydrophilic polymer, such as dextran. These particles are used for MRI scanning of the liver or lymphatic ganglions. They are generally designated by (U)SPIO [(Ultrasmall) SuperParamagnetic Iron Oxide] and they are described in particular by Neuberger et al [J. Magn. Magn. Mat., 293 (2005) 483]. They are prepared by coprecipitation of iron oxide directly in an aqueous solution of the preformed polymer as described in U.S. Pat. No. 4,452,773. In these materials there is no covalent bond between the maghemite and the polymer. The polymer coating is therefore sensitive to phenomena of desorption/depletion. In order to improve the quality of these particles, it has been proposed to cross-link the dextran around the nanoparticles (U.S. Pat. No. 5,262,176) or to cross-link the dextran by means of iron oxide nanoparticles previously modified at the surface by an aminosilane-type derivative (FR-2,855,315). The principal drawback of these methods according to the prior art is the number of steps in the chemical modification and the fact that each modification step necessitates a very long purification step since it is essentially effected by dialysis. Furthermore, dextran is not very effective for limiting the adsorption of plasma proteins and therefore extending the half-life of the nanoparticles.
It is known that polyethylene oxide PEO is an effective surfactant for increasing the plasma half-life of particles, in particular when it is in telechelic form, for example a polyethylene glycol PEG. However, the grafting ratio of PEO on the surface of the nanoparticles is poor. Indeed, the steric hindrance resulting of the polymer chains around a particle limits the quantity of polymer which is fixed on the particle due to the fact that access to the active sites of the particle surface is limited. For example, Butterworth et al, [Surf. A, 179, 93 (2001)], describe such particles for which the maximum PEG content is 9% by mass. Furthermore, Davis et al, [Coll Surf A: Physicochem. Eng. Aspects, 179 (2001) 93], describe the grafting onto magnetic oxide particles of polyethylene oxide (PEO) chains which are preformed and functionalised by an organosilane group. This technique exhibits the same drawbacks as the one described by Butterworth as mentioned above. Furthermore, the preformed chains are generally obtained by a method using a catalyst and they contain residues of this catalyst which may be toxic for medical applications of the modified particles.